This research proposal is a combined basic and clinical investigation on the exactness of DNA synthesis in human lmphocytes. The overall objective is to determine whether malignant cells synthesize DNA with less accuracy than normal cells. Our aims are: 1) To further define the fidelity with which human DNA polymerases copy polynucleotide templates of defined composition. 2) To determine if there are nuclease(s) present in human lymphocytes that excise mismatched bases during the course of DNA replication. 3) To develop assays for measuring the accuracy with which DNA polymerases copy natural DNA templates. 4) To study the effects of chemical carcinogens and chemical mutagens on the fidelity of DNA synthesis using model in vitro systems. 5) To determine if errors in DNA synthesis or deficiencies in DNA repair are associated with the onset and progression of leukemia.